Microglia are known as macrophages of the brain, and as part of the innate immune system they constantly monitor the integrity of the central nervous system (CMS) and respond quickly to insults. Microglia can initiate both inflammatory and anti-inflammatory immune responses, but the mechanisms and signals that activate microglia towards either state are poorly understood. Only a few receptors related to cellular activation or inhibition have been identified on microglia. Triggering receptor expressed on myeloid cells-2 (TREM2) and DAP12 are a receptor complex expressed on the cell surface of microglia, and has been previously characterized as an immunoregulatory molecule on myeloid-derived cells, such as macrophages, immature dendritic cells, and microglia. The TREM2-DAP12 complex is critical to prevent a rare neurodegenerative disease called Nasu-Hakola disease, but ligands and/or cells that stimulate TREM2 are unknown. There is evidence to suggest that TREM2 may be activated by signals from apoptotic neuronal cells that induce phagocytosis by microglia without inducing inflammation. Our specific aims are to demonstrate the function of TREM2 on microglia upon engagement with ligands expressed on neurons in vitro and in vivo. Our work will explore the importance of TREM2 during the neurodegenerative disease, Parkinson's disease, which is one of the most common neurodegenerative disorders where excessive microglial inflammatory responses are considered harmful. The long-term objectives of this project are to elucidate the role of TREM2 on microglia, and to understand the importance of this receptor during neuroinflammation and neurodegeneration, and improve human health. The significance of understanding the role of TREM2 may be applied to multiple neurological and immunological diseases. [unreadable] [unreadable]